1. Field of the Invention
The present invention generally relates to a method of inhibiting adrenocorticotropin (ACTH) secretion and, more particularly, to using an atrial natriuretic factor (ANF) with an intact N-terminal sequence to inhibit corticotropin releasing factor (CRF 41) induced ACTH secretion.
2. Description of the Prior Art
Current research suggests that the brain pituitary adrenal cascade of stress hormones may mediate stress induced disease in humans and animals. Partial immunosuppression, one of the proposed mechanisms, may increase the susceptibility to infectious disease and lead to tumor development; therefore, an inhibitor of inappropriate stress hormone secretion during psychological and emotional stress may find widespread use in preventive medicine. In addition, stress hormone inhibitors may be useful in animal husbandry because excessive release of stress hormones may lead to stunted growth in domestic animals.
ANF is a family of polypeptides, all of which have a common amino acid sequence, but differ in length by the presence or absence of 1-8 amino acids on the amino or carboxyl termini (N-terminal or C-terminal, respectively). ANF peptides are bio-active hormonal substances which are synthesized in cardiac atria. U.S. Pat. No. 4,663,437 to de Bold discloses that extracts of ANF peptides play a role in extracellular fluid volume regulation. Shortly after administration, the extract enhances urinary flow and increases urinary sodium, potassium, and chloride excretion. U.S. Pat. No. 4,607,023 to Thibault et al discloses synthesized ANF peptides having diuretic, natriuretic, vasorelaxant, hypotensive or antihypertensive properties. These synthesized ANF peptides are administered systemically, either by intravenous, subcutaneous, or intramuscular injection, or by sublingual or nasal administration.
U.S. Pat. No. 4,643,989 to Baird discloses atrial peptides, which are ANF-like polypeptides, that inhibit aldosterone secretion. These peptides or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid, can be administered to mammals in order to inhibit basal aldosterone secretion and thereby manage aldosterone dependent hypertension.
The secretion of ACTH is ultimately controlled by the hypothalamus. In response to stress situations, the hypothalamus secretes CRF which is sent to the anterior pituitary and stimulates it to release ACTH into the blood. ACTH binds to receptors on cells of the adrenal cortex, stimulating the production of steroid hormones, which are mainly cortisol (in humans) and corticosterone (in rats). To date, there is no generally accepted ACTH-release inhibitor.
U.S. Pat. No. 4,605,642 to Rivier et al discloses polypeptide analogs that are competitive antagonists of CRF 41 in mammals. These antagonists or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals, including humans, to prevent the elevation of ACTH. They may be used to affect mood, memory and learning, as well as diagnostically. In an article by the same inventors, alpha helical ovine CRF 9-41 was shown to blunt stress induced ACTH release in non-anesthetized rats (see, Rivier et al, Science 224, pp. 889-891 (1984)). However, very high concentrations (micromolar) are required to block CRF 41 induced ACTH secretion. Moreover, CRF 9-41 is a large peptide which is costly to produce in large quantities and is difficult to introduce into the blood stream by non-invasive means.
Okajima et al have disclosed that delta sleep inducing peptide (DSIP) inhibits CRF induced ACTH secretion from the rat anterior pituitary gland in vitro (see, Okajima et al, Horm. Metab. Res. 18, pp. 497-498 (1986)). Okijima et al found that 10 nanomolar (nM) DSIP was the most effective concentration for inhibition of ACTH secretion. It is difficult and costly to maintain such high concentrations of peptides in the blood stream because of their short half life due to enzymatic cleavage.